A preparation method of butyl remdesivir

Abstract

The present invention provides a novel method for synthesizing butyl remdesivir, that is, remdesivir shown in formula II reacts with butanol or a mixture of butanol and an organic solvent in the presence of a base, and butyl remdesivir shown in formula I is obtained by separation. The method of the present invention uses easily available remdesivir as a reaction substrate, and the target product can be obtained in one chemical reaction step. The separation step is simple and easy to operate, and the yield can reach 87%, which is greatly improved compared with the prior art. At the same time, the butyl remdesivir obtained by the present invention has a high purity, which can reach more than 99%.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and in particular relates to a method for preparing butyl remdesivir, a new impurity of remdesivir. Background Art

[0002] Remdesivir (GS-5734) is a broad-spectrum antiviral drug that can prevent viruses from replicating themselves and has a wide range of inhibitory effects on arenaviruses, filoviruses and coronaviruses. Its chemical name is ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrole[1,2-b]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine-2-ethylbutyl ester, and its structural formula is as follows:

[0003]

[0004] In the synthesis process of remdesivir API, we found that an unknown impurity is easily produced under normal process conditions, especially when some process parameters are not well controlled. The content of this impurity in some abnormal batches of remdesivir crude products is as high as 0.7%, and the removal effect of this impurity in the subsequent refining process is poor. Therefore, it is necessary to investigate the impurity, analyze its structure, and synthesize the impurity reference substance for subsequent quality research and provide guidance for process parameter adjustment. Through high-resolution mass spectrometry liquid chromatography-mass spectrometry (LC-HRMS) and nuclear magnetic resonance structural characterization, it was determined that the unknown impurity in the remdesivir process is butyl remdesivir, and its structural formula is shown in Formula I:

[0005]

[0006] CN112321642A discloses a method for synthesizing butyl remdesivir, which uses butanol to replace the starting material 2-ethylbutanol and refers to the method of remdesivir synthesis process. Butyl remdesivir is synthesized through 4 steps of chemical reactions. The chemical synthesis has many steps, the route is very long, and the yield is very low. Summary of the invention

[0007] The preparation method of the prior art needs to use butanol instead of the starting material 2-ethylbutanol to synthesize butyl remdesivir through 11 steps of chemical reactions. The route is very long and needs to go through the following steps: condensation, cyanation, hydrogenation to remove the benzyl protecting group, phosphation, chiral separation, etc., and the yield is very low. The present invention provides a new method for synthesizing butyl remdesivir, that is, under alkaline conditions, remdesivir shown in formula II and butanol or a mixture of butanol and an organic solvent undergoes an ester exchange reaction in the presence of a base, and butyl remdesivir shown in formula I is obtained by separation.

[0008] A method for preparing butyl remdesivir shown in formula I, the reaction formula of which is as follows:

[0009]

[0010] Furthermore, in the above preparation method, the organic solvent is a polar organic solvent, preferably one of tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, dimethyl sulfoxide or N-methylpyrrolidone.

[0011] Furthermore, in the above preparation method, the base is an inorganic base or an organic base, or any combination thereof, wherein the inorganic base is selected from one of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, tetramethylammonium hydroxide, sodium phosphate, potassium phosphate, sodium hydride or potassium hydride, preferably one of sodium hydroxide, potassium hydroxide or sodium hydride; the organic base is selected from one of sodium methoxide, sodium ethoxide, sodium butoxide, potassium butoxide, potassium tert-butoxide, tetrabutylammonium hydroxide or tetramethylammonium hydroxide, preferably one of potassium tert-butoxide, tetramethylammonium hydroxide or tetrabutylammonium hydroxide.

[0012] Furthermore, in the above preparation method, the molar ratio of the base to remdesivir is 1:1 to 50:1, preferably 1.5:1 to 10:1.

[0013] Furthermore, in the above preparation method, the mass volume ratio (g / mL) of remdesivir to butanol is 0.5:1 to 100:1, preferably 5:1 to 30:1.

[0014] Furthermore, in the above preparation method, when the reaction condition is a mixture of butanol and an organic solvent in the presence of a base, the volume ratio of the butanol to the organic solvent is 0.01:1 to 10:1, preferably 0.1:1 to 1:1.

[0015] Furthermore, in the above preparation method, the reaction temperature is -10 to 80°C, preferably 10 to 45°C, and the reaction time is 0.1 to 36 hours, preferably 0.5 to 5 hours.

[0016] Compared with the prior art, the present invention has the following advantages:

[0017] The original technical method CN112321642A discloses a method for synthesizing butyl remdesivir, and its synthesis uses butanol to replace the starting material 2-ethylbutanol and refer to the method of remdesivir synthesis process, but it needs to undergo 4 steps of chemical reaction to synthesize butyl remdesivir, and there are many chemical synthesis steps, the route is very long, and the yield is very low, only about 3%. The present invention uses easily available remdesivir as a reaction substrate, and the target product can be obtained in one chemical reaction step. The separation step is simple, easy to operate, and the yield can reach 87%, which is greatly improved compared with the prior art; at the same time, the butyl remdesivir obtained by the present invention has a high purity, which can reach more than 99%. DETAILED DESCRIPTION

[0018] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. Based on the examples in the present invention, any changes and modifications of the present invention by those skilled in the art without creative work shall fall within the protection scope of the present invention.

[0019] The raw material preparation method, preparative liquid chromatography method and general chromatography detection method are as follows:

[0020] The remdesivir raw material used in the examples was prepared according to Journal of Medicinal Chemistry, 60 (2017) 1648-1661.

[0021] General detection method:

[0022] Instrument: High performance liquid chromatography equipped with UV detector

[0023] Chromatographic column: ACEExcel 3C18, 150*4.6mm, 3μm

[0024] Mobile phase A: 10 mmol / L ammonium formate aqueous solution, pH adjusted to 5 with formic acid

[0025] Mobile phase B: acetonitrile

[0026] Detection wavelength: 240nm

[0027] Flow rate: 1.0mL / min

[0028] Column temperature: 30°C

[0029] Run time: 45 minutes

[0030] gradient:

[0031]

[0032] Example 1

[0033] 1.0 g of remdesivir was added to 20 mL of n-butanol and 20 mL of anhydrous tetrahydrofuran, followed by the addition of 0.67 g of sodium hydroxide, and the reaction was carried out at 30°C for 2 hours. After the reaction, an appropriate amount of dilute hydrochloric acid was added to adjust the pH value of the solution to 3.0. The treated solution was lyophilized with a freeze dryer, and the obtained solid was separated from the target product by column chromatography [HP-Silica normal phase silica gel, eluent: dichloromethane: methanol = (20:1, v / v)], and finally 0.74 g of butyl remdesivir was obtained, with an HPLC purity of 99.2% and a yield of 78%.

[0034] Example 2

[0035] 1.0 g of remdesivir was added to 10 mL of n-butanol, followed by 0.37 g of potassium tert-butoxide, and the mixture was reacted at 40 °C for 2 hours. After the reaction, an appropriate amount of dilute hydrochloric acid was added to adjust the pH value of the solution to 3.0. The treated solution was lyophilized using a freeze dryer, and the obtained solid was separated from the target product using a column chromatography method [HP-Silica normal phase silica gel, eluent: dichloromethane: methanol = (20:1, v / v)] to finally obtain 0.81 g of butyl remdesivir with an HPLC purity of 98.3% and a yield of 85%.

[0036] Example 3

[0037] 1.0 g of remdesivir was added to 20 mL of n-butanol, followed by 0.24 g of sodium hydride (mass fraction 50%), and the mixture was reacted at 30°C for 2 hours. After the reaction, an appropriate amount of dilute hydrochloric acid was added to adjust the pH value of the solution to 3.0. The treated solution was lyophilized using a freeze dryer, and the obtained solid was separated from the target product using a column chromatography method [HP-Silica normal phase silica gel, eluent: n-dichloromethane: methanol = (25:1, v / v)], and finally 0.80 g of butyl remdesivir was obtained, with an HPLC purity of 99.4% and a yield of 84%.

[0038] Example 4

[0039] 1.0 g of remdesivir was added to 5 mL of n-butanol and 20 mL of anhydrous 1,4-dioxane, followed by the addition of 0.28 g of sodium hydride (mass fraction 50%), and the mixture was reacted at 40°C for 2 hours. After the reaction, an appropriate amount of dilute hydrochloric acid was added to adjust the pH value of the solution to 3.0. The treated solution was then freeze-dried using a freeze dryer, and the obtained solid was separated from the target product using a column chromatography method [HP-Silica normal phase silica gel, eluent: dichloromethane: methanol = (30:1, v / v)], and finally 0.75 g of butyl remdesivir was obtained, with an HPLC purity of 99.5% and a yield of 79%.

[0040] Example 5

[0041] 1.0 g of remdesivir was added to 10 mL of n-butanol and 20 mL of anhydrous 1,4-dioxane, followed by the addition of 0.37 g of potassium tert-butoxide, and the reaction was carried out at 30°C for 4 hours. After the reaction, an appropriate amount of dilute hydrochloric acid was added to adjust the pH value of the solution to 3.0. The treated solution was then freeze-dried with a freeze dryer, and the residue was separated by column chromatography [HP-Silica normal phase silica gel, eluent: dichloromethane: methanol = (12:1, v / v)] to obtain 0.83 g of butyl remdesivir, with an HPLC purity of 99.2% and a yield of 87%.

[0042] Example 6

[0043] 1.0 g of remdesivir was added to 20 mL of n-butanol and 20 mL of N,N-dimethylformamide, followed by the addition of 0.32 g of sodium hydride (mass fraction 50%), and the mixture was reacted at 30°C for 2 hours. After the reaction, an appropriate amount of dilute hydrochloric acid was added to adjust the pH value of the solution to 3.0. The treated solution was then freeze-dried using a freeze dryer, and the residue was separated by column chromatography [HP-Silica normal phase silica gel, eluent: dichloromethane: methanol = (20:1, v / v)] to obtain 0.77 g of butyl remdesivir with an HPLC purity of 99.3% and a yield of 81%.

[0044] Example 7

[0045] 1.0 g of remdesivir was added to 10 mL of n-butanol and 20 mL of N-methylpyrrolidone, followed by the addition of 0.33 g of sodium hydroxide, and the mixture was reacted at 30°C for 2 hours. After the reaction, an appropriate amount of dilute hydrochloric acid was added to adjust the pH value of the solution to 3.0. The treated solution was then freeze-dried using a freeze dryer, and the residue was separated by column chromatography [HP-Silica normal phase silica gel, eluent: dichloromethane: methanol = (30:1, v / v)] to obtain 0.71 g of butyl remdesivir with an HPLC purity of 99.5% and a yield of 75%.

[0046] Example 8

[0047] 1.0 g of remdesivir was added to 20 mL of n-butanol, followed by 0.46 g of potassium hydroxide, and the mixture was reacted at 50°C for 1 hour. After the reaction, an appropriate amount of dilute hydrochloric acid was added to adjust the pH value of the solution to 3.0. The treated solution was lyophilized using a freeze dryer, and the residue was separated by column chromatography [HP-Silica normal phase silica gel, eluent: dichloromethane: methanol = (25:1, v / v)] to obtain 0.74 g of butyl remdesivir with an HPLC purity of 98.6% and a yield of 78%.

Claims

1. A method for preparing butyl remdesivir shown in formula I, characterized in that The reaction formula of the preparation method is as follows: The remdesivir shown in formula II and butanol or a mixture of butanol and an organic solvent undergo an ester exchange reaction in the presence of a base, and butyl remdesivir shown in formula I is obtained by separation.

2. A method for preparing butyl remdesivir as shown in formula I according to claim 1, characterized in that The organic solvent is a polar organic solvent.

3. A method for preparing butyl remdesivir as shown in formula I according to claim 2, characterized in that The polar organic solvent is one of tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, dimethyl sulfoxide or N-methylpyrrolidone.

4. A method for preparing butyl remdesivir represented by formula I according to claim 1, characterized in that The base is an inorganic base or an organic base, or any combination thereof, wherein the inorganic base is selected from one of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, sodium phosphate, potassium phosphate, sodium hydride or potassium hydride; and the organic base is selected from one of sodium methoxide, sodium ethoxide, sodium butoxide, potassium butoxide, potassium tert-butoxide, tetrabutylammonium hydroxide or tetramethylammonium hydroxide.

5. A method for preparing butyl remdesivir represented by formula I according to claim 4, characterized in that The inorganic base is one of sodium hydroxide, potassium hydroxide or sodium hydride; the organic base is one of potassium tert-butoxide, tetramethylammonium hydroxide or tetrabutylammonium hydroxide.

6. A method for preparing butyl remdesivir represented by formula I according to claim 1, characterized in that The molar ratio of the base to remdesivir is 1:1 to 50:

1.

7. A method for preparing butyl remdesivir of formula I according to claim 6, characterized in that The molar ratio of the base to remdesivir is 1.5:1 to 10:

1.

8. A method for preparing butyl remdesivir represented by formula I according to claim 1, characterized in that The mass volume ratio of remdesivir to butanol g / mL is 0.5:1 to 100:

1.

9. A method for preparing butyl remdesivir represented by formula I according to claim 8, characterized in that The mass volume ratio of remdesivir to butanol g / mL is 5:1 to 30:

1.

10. A method for preparing butyl remdesivir of formula I according to claim 1, characterized in that The reaction temperature is -10 to 80°C, and the reaction time is 0.1 to 36 hours.

11. A method for preparing butyl remdesivir of formula I according to claim 10, characterized in that The reaction temperature is 10-45° C., and the reaction time is 0.5-5 hours.

12. The method for preparing butyl remdesivir of formula I according to claim 1, characterized in that: When the reaction condition is a mixture of butanol and an organic solvent in the presence of a base, the volume ratio of the butanol to the organic solvent is 0.01:1 to 10:

1.

13. A method for preparing butyl remdesivir represented by formula I according to claim 12, characterized in that: When the reaction condition is a mixture of butanol and an organic solvent in the presence of a base, the volume ratio of the butanol to the organic solvent is 0.1:1 to 1:1.

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